Patients with extensive ulcerative colitis (UC) have a substantially increased risk of colon cancer. The current screening recommendations, which require frequent colonoscopic surveillance of these patients, are expensive, time consuming, and invasive. An objective biomarker of dysplasia would have great clinical value in the management of cancer risk in UC patients. UC-associated cancer progresses from dysplasia to cancer and is associated with mitochondrial dysfunction, which has long been associated with degenerative diseases, cancer, and aging. Our recent proteomics studies reveal that mitochondrial proteins are involved in UC neoplastic progression and could be valuable targets for biomarker development. The objectives of this research are to better understand the role of mitochondrial proteins underlying the neoplastic progression in chronic UC; and further, to employ this knowledge for improved, more cost effective surveillance-to differentiate the subset of UC patients who need colonoscopy from those who do not. In the proposed study, cutting-edge quantitative proteomics and bioinformatics technologies will be applied to discover aberrant mitochondrial proteins that are associated with precursor lesions during UC neoplastic progression (Aim 1). The identified aberrant mitochondrial proteins will be complementarily characterized using immunochemistry (Aim 2) and targeted proteomics (Aim 3). This project may lead to the discovery of protein biomarkers with direct clinical utility in decision-making for colonoscopy and thus could potentially reduce the cost and patient discomfort associated with colonoscopy. Moreover, the proposed comprehensive analysis of mitochondrial proteome will improve the understanding of the mitochondrial proteome in cancer progression, an area for which we currently have very limited information. The study described is based on our unique resource of material obtained from ulcerative colitis patients and the close-knit collaboration of investigators who have been working together for more than ten years. Successful completion of this proposal will lead to: 1) better understanding of alterations in mitochondrial proteome in UC associated dysplasia and cancer; 2) identification of biomarker candidates to predict UC dysplasia, providing a less invasive, cost effective method to assist UC cancer surveillance. PUBLIC HEALTH RELEVANCE: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon that can eventually cause colon cancer. Because of this, patients with extensive UC require colonoscopy every 2-3 years to look for cancer and pre-cancer. Mitochondria are important organelles that generate most of the energy a cell needs, and abnormal mitochondria have been associated with cancer. Discovery and characterization of alterations in mitochondria associated with UC cancer and pre-cancers could lead to the development of cancer biomarkers. Such biomarkers could be used to help decide which UC patients should have a colonoscopy and which don't need it. This would greatly reduce costs to society and patient discomfort, and improve the ability to target high-risk patients who need intervention.